Founder effects and genetic drift may increase the frequency of recessive mutations, particularly in small or rapidly growing (e.g., prehistoric) populations. However, such chance effects are unlikely to have occurred in the comparatively large populations that have resided in Europe over the last 3,000–5,000 years. Without a mechanism counteracting the constant loss of recessive disease alleles from these peoples, the frequency of PKU would have fallen to a fraction of its current value. To demonstrate this formally, let us assume all disease-causing PAH gene
Founder effects and genetic drift ruled out to explain the frequency of PKU. Drift is typically most significant in small populations. Since large populations resided in Europe over the last 3,000-5,000 years, these chance event are unlikely.
Rule out drift
Despite suggestions to the contrary [Scriver and Kaufman, 2001], at least three different aspects of genetic drift argue against a strong stochastic component in the extant PKU-associated mutational spectrum of the PAH gene.
- First, genetic drift would have affected only singular mutant alleles, not a large
number of mutations.
- Second, drift would have been operating in certain populations, but not in all
populations at the same time.
- Finally, drift would have been equally likely to affect PAH gene mutations
causing PKU and mutations in other genes causing other recessive disorders.
The available molecular and epidemiological data corroborate none of these corollaries so that chance events alone cannot convincingly explain the high incidence of PKU in Europe.
Overdominant selection (‘‘heterozygote advantage/Heterosis’’)
Overdominant selection thus appears to have played an important role during the history of PKU in European populations, although the exact nature of this effect is still unknown. In any case, its magnitude is likely to have been small because, under balancing selection, the equilibrium disease allele frequency qe is approximately equal to the heterozygous effect h [Gillespie, 1998]. The most likely heterozygote advantage of PKU, therefore, amounts to 1–1.5% and is thus difficult to measure empirically. At the biochemical level, overdominant selection in PKU is probably a consequence of higher phenylalanine levels in heterozygotes than in nonheterozygotes [Woolf et al., 1967]. This elevated amino acid concentration nevertheless must have been advantageous under different climatic conditions and against the back- ground of different diets and social circumstances. A number of possible albeit controversial selective mechanisms have been discussed [Vogel, 1984]. Thus, female carriers of PKU could be shown both to have lower [Woolf et al., 1975; Woolf, 1976, 1978] and higher [Saugstad, 1973; Blyumina, 1974] rates of spontaneous miscarriages than controls. In addition, birth weight in the nonaffected children of PKU carriers has been reported to be increased [Saugstad, 1977], although not consistently so [Smith et al., 1978], when compared to control children. Ochratox- in A, a mycotoxin found in moldy grains and lentils that can induce spontaneous abortions [Dirheimer and Creppy, 1991], has been proposed as a selective agent for PKU [Woolf, 1986]. Furthermore, increased phenylalanine levels caused by protein catabolism at times of starvation [Blyumina, 1981] could have exerted a protective effect in PKU carriers. Although there is currently no evidence supporting this hypothesis, it is certainly possible that overdominant selection in PKU occurred predominantly during periods of epidemics or famine, of which there are many examples in European history.
Heterosis appears to play an important role in European populations. According to the article its magnitudes is likely to have been small and difficult to measure empirically. They suggest that heterosis in PKU is a consequence of higher phenylalanine levels in heterozygotes than in non. This would suggest an elevated AA concentration must have been advantageous under different climatic conditions and against different diets and social circumstances. As stated in the earlier post, female carriers of PKU could be shown to have lower rates of spontaneous miscarriages. Also, this article reported an increase in birth weight of nonaffected children of PKU carriers which would help an infant survive. Finally, increased phenylalanine levels seen with individuals that have PKU could have exerted an protective effect in PKU carriers during periods of epidemics or famine throughout European history.
Retrieved from:
Krawczak, M., & Zschocke, J. (2003). A role for overdominant selection in phenylketonuria? Evidence from molecular data. Human Mutation, 21(4), 394-397.
PKU 